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Patients with Mutations in Gs Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

Departments of Pediatric Endocrinology (S.C.H., E.L.G.-L.), Pulmonary and Critical Care Medicine (C.A.M., M.P.B.), and Pediatric Pulmonology (P.L.Z.) and Institute of Genetic Medicine (J.D.G., K.N., G.R.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Stephanie C. Hsu, M.D., Ph.D., Johns Hopkins University, 733 North Broadway, Suite 551, Baltimore, Maryland 21205. E-mail: shsu8{at}jhmi.edu.

Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues.

Objective: The objective of the study was to gain insight into the downstream consequences of abnormal stimulatory G protein signaling in human epithelial tissues.

Patients and Design: We assessed transcription of GNAS and Gs-stimulated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in AHO patients, compared with normal controls and patients with cystic fibrosis.

Main Outcome Measures: Relative expression of Gs transcripts from each parental GNAS allele and cAMP measurements from nasal epithelial cells were compared among normal controls and AHO patients. In vivo measurements of CFTR function, pulmonary function, and pancreatic function were assessed in AHO patients.

Results: GNAS was expressed equally from each allele in normals and two of five AHO patients. cAMP generation was significantly reduced in nasal respiratory epithelial cells from AHO patients, compared with normal controls (0.4 vs. 0.6, P = 0.0008). Activation of CFTR in vivo in nasal (P = 0.0065) and sweat gland epithelia (P = 0.01) of AHO patients was significantly reduced from normal. In three patients, the reduction in activity was comparable with patients with cystic fibrosis due to mutations in CFTR. Yet no AHO patients had pulmonary or pancreatic disease consistent with cystic fibrosis.

Conclusions: In humans, haploinsufficiency of GNAS causes a significant reduction in the activation of the downstream target, CFTR, in vivo.